EP0851855B9 - Acylierte derivate von melatonin und dessen analoge als arzneimittel - Google Patents

Acylierte derivate von melatonin und dessen analoge als arzneimittel Download PDF

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EP0851855B9
EP0851855B9 EP96928490A EP96928490A EP0851855B9 EP 0851855 B9 EP0851855 B9 EP 0851855B9 EP 96928490 A EP96928490 A EP 96928490A EP 96928490 A EP96928490 A EP 96928490A EP 0851855 B9 EP0851855 B9 EP 0851855B9
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Prior art keywords
radical
ethyl
methoxyindol
acetyl
acetamide
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EP0851855A1 (de
EP0851855B1 (de
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Jean-Bernard Fourtillan
Marianne Fourtillan
Jean-Claude Jacquesy
Marie-Paule Jouannetaud
Bruno Violeau
Omar Karam
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Macef SAS
Laboratoires Besins International SAS
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BESINS ISCOVESCO LAB
Macef SAS
Laboratoires Besins International SAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/18—Feminine contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/30—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms
    • C07C233/31—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2

Definitions

  • the present invention relates to agonist derivatives melatoninergics, their preparation process and their use as drug.
  • Melatonin N-acetyl-5-methoxytryptamine, is a hormone from the pineal gland, isolated by Lerner et al . (J.am.Chem.Soc., 80, 1958, 2587), which has been the subject of numerous studies for its circadian activity, in the rhythm of sleep, for its effects on testosterone production, for its activity in level of the hypothalamus and in psychiatric disorders.
  • melatonin and its analogs in particular for the treatment of depression and psychiatric disorders, particularly stress, anxiety, depression, insomnia, schizophrenia, psychosis, epilepsy, but also for the treatment of travel-related sleep disorders ("jet lag "), neurodegenerative diseases of the central nervous system such as Parkinson's disease or Alzheimer's disease, for the treatment of cancers, or again as a contraceptive, or as an analgesic.
  • EP 527 687 and EP 585 206 describe compounds of formulas general related to that of the compounds of the present application as well as the use of these compounds for the treatment of circadian rhythm disorders and sleep and seasonal disorders.
  • the present patent application proposes a new development path melatonin analogs with improved activity.
  • EP 527 687 which relates to derivatives of arylethylamines having an agonist or antagonist character of melatonin.
  • EP 585 206 and US 5 403 851 relate to derivatives of tryptamines and phenalkylamines for the treatment of pathologies linked to arrhythmia Circadian.
  • alkyl alkoxy or perhaloalkyl
  • radicals in which the alkyl residue contains between 1 and 6 carbon atoms are generally meant radicals in which the alkyl residue contains between 1 and 6 carbon atoms.
  • C 1 -C 4 alkyl radicals More particularly chosen from methyl, ethyl, n-propyl, i-propyl, n-butyl or t-butyl groups.
  • cycloalkyl is meant C 3 -C 6 rings.
  • aryl denotes a group chosen from phenyl, thienyl, furanyl, pyridyle or naphthyle.
  • Aryl radicals can also be substituted by one or more substituents chosen from the alkyl, alkoxy or halogeno radicals defined above.
  • aralkyl is meant the combination of alkyl and aryl such that defined above. It will preferably be the benzyl radical.
  • halo radicals are preferably chosen from atoms of fluorine, bromine chlorine or iodine.
  • the perhalogenated radicals are perfluorinated radicals.
  • the present invention also relates to racemic derivatives of general formula I, as well as its pure enantiomers, or their mixtures in all proportions.
  • the therapeutically acceptable salts of the derivatives according to the invention are the usual salts of the technique, organic or inorganic, in particular the hydrochlorides, tosylates, mesilates, citrates as well as solvates such as hydrates or hemihydrates of the compounds of general formula I.
  • the present invention relates more particularly to derivatives of general formula I for which W represents an oxygen atom.
  • At least one of the substituents R2 or R3 is different from a hydrogen atom and preferably represents a hydroxyl or alkoxy radical in which the alkyl residue is C 1 -C 6 , in particular a methoxy radical.
  • R1, R4 and R6 represent an atom hydrogen.
  • R5 is advantageously a C 1 -C 6 alkyl radical, preferably methyl, ethyl, n-propyl or a perfluoromethyl, perfluoroethyl or perfluoropropyl radical, preferably perfluoroethyl.
  • R7 represents an alkyl- (C 1 -C 6 ) -carbonyl radical.
  • the present invention also relates to the process for the preparation of derivatives of general formula I as defined above.
  • the derivatives according to the present invention can be obtained by reacting the corresponding amine of general formula II. Y, R1 to R4, R6 and R7 being defined above, with an appropriate acylating agent, according to the usual techniques for the preparation of amides, so as to introduce the radical - CW - R5 W representing an oxygen atom and R5 being defined above, with the corresponding halide or anhydride, or alternatively with an activation of the corresponding acid with optionally a coupling agent, as used in peptide synthesis.
  • the derivatives for which R5 and R6 together form part of a cycle of formula - (CH 2 ) m -CW'-, with W 'representing an oxygen atom are prepared by acylating the derivative of general formula II for which R6 represents a hydrogen atom with an appropriate acylating agent so as to introduce the radical -CW '- (CH 2 ) m -CW - O - alkyl, W representing an oxygen atom and m being defined above, then cyclizing the amide obtained by an appropriate reaction, for example by acid catalysis in the presence of traces of paratoluenesulfonic acid in xylene.
  • the derivative obtained previously can then be transformed to obtain a new derivative of general formula I for which R6 is different from a hydrogen atom.
  • Example 2 The procedure of Example 2 is repeated with the starting product 1-methylene-2-propionyl-6-methoxy) -1,2,3,4-tetrahydro- ⁇ -carboline.
  • 1 H NMR CD 3 COOD 3 : 1.76 (t, 3H, CH 3 Ethyl); 2.23 (t, 2H, CH 2 ethyl); 2.72 (s, 3H, CH 3 CO in position 2 indole); 3.40 (t, 2H, CH 2 ); 3.57 (q, 2H, CH 2 N); 3.95 (s, 3H, CH 3 O); 7.10 (dd, 1H, H-6); 7.20 (br s, 1H, NHCO); 7.40 (d, 1H, H-4); 7.5 (d, 1H, H-7); 10.6 (broad s, 1H, NH indole); SM: m / z 288 (M + ⁇ ), 245, 215 (100), 202, 188. Exact mass: Calculated 288.1473 Found
  • Example 2 The procedure of Example 2 is repeated with the starting product 1-methylene-2-acetyl-1,2,3,4-tetrahydro- ⁇ -carboline.
  • CD 3 COCD 3 1.84 (s, 3H, CH 3 CO-N ⁇ ); 2.30 and 2.94 (2m, 2H, CH 2 ), 2.57 (s, 3H, CH 3 CO-N ⁇ ); 3.25 and 3.47 (2m, 2H, CH 2 -N); 3.76 (t, 1H, H-3); 3.80 (s, 3H, CH 3 O); 6.57 (d, 1H, H-6); 7.09 (s, 1H, H-4); 8.03 (d, 1H, H-7); 7.22 (br s, 1H, NH).
  • a mixture of 5-methoxytryptamine (420 mg) is heated to 175 ° C. and diethyl glutarate (460 mg), for 18 h.
  • Column separation (eluent AcOEt) provides the corresponding ester amide.
  • N- [2- (2-cyclohexylcarbonyl-5-methoxyindol-3-yl) ethyl] acetamide (8) is obtained.
  • N- [2- (2-acetyl-5-methoxyindol-3-yl) ethyl] diacetamide (9) is a secondary product of the acylation reaction of melatonin according to the method of Example 4, procedure b , isolated by flash chromatography.
  • N- [2- (5-methoxyindol-3-yl) ethyl] glutarimide 145 mg N- [2- (5-methoxyindol-3-yl) ethyl] glutarimide are dissolved in DMSO (30 ⁇ l) in a flask, and concentrated HCl (72 ⁇ l) is added with stirring. The whole is stirred overnight at room temperature. The crude is neutralized with NH 3 , then extracted with AcOEt. After separation on a silica plate, N- [2- (5-methoxy-2-oxo-2,3-dihydroindol-3-yl) ethyl] glutarimide is obtained.
  • N- [2- (6-acetyl-5-methoxyindol-3-yl) ethyl] acetamide is prepared by alkaline hydrolysis of N- [2- (6-acetyl-1-carbethoxy-5-methoxyindol-3-yl) ethyl] acetamide in alcoholic potash.
  • N- [2- (5-methoxyindolin-3-yl) ethyl] acetamide is carried out by the method described for the synthesis of N- [2- (1-acetyl-5-methoxyindolin-3-yl) ethyl ] acetamide.
  • the N- [2- (1-benzyloxycabonyl-5-methoxyindolin-3-yl) ethyl] acetamide intermediate is prepared by reacting the N- [2- (5-methoxyindolin-3-yl) ethyl] acetamide on chloroformate d ethyl in dichloromethane at 0 ° C in the presence of triethylamine.
  • the final acylation is carried out with acetic anhydride, at the reflux of toluene for 24 hours, and makes it possible to obtain N- [2- (1-triluoromethanesulfonyl-5-methoxyindolin-3-yl) ethyl] diacetamide.
  • N- [2- (5-methoxyindolin-3-yl) ethyl] acetamide is carried out by the method described for the synthesis of N- [2- (1-acetyl-5-methoxyindolin-3-yl) ethyl ] acetamide.
  • N- [2- (1-triluoromethanesulfonyl-5-methoxyindolin-3-yl) ethyl] acetamide intermediate is prepared by reacting the N- [2- (5-methoxyindolin-3-yl) ethyl] acetamide on the anhydride trifluoromethanesulfonic acid in dichloromethane at -78 ° C in the presence of triethylamine.
  • N- [2- (1-carbethoxy-2-acetyl-5-methoxyindol-3-yl) ethyl] acetamide 100 mg is dissolved in ethanol (10 ml) . 100 mg of Pd (OH) 2 are added , the whole is stirred for 12 h under normal hydrogen pressure. After filtration, N- [2- (1-carbethoxy-2-acetyl-5-methoxyindolin-3-yl) ethyl] acetamide is obtained.
  • the live weights of the chicks varied between 95 and 155 g.
  • the tests are carried out from 2 p.m.
  • the chicks are allotted in groups of 3 in identical vivariums of 30 cm x 50 cm x 30 cm.
  • the tested products are administered intramuscularly (IM) in the major pectoral muscle, in hydro-ethanolic solution (mixture ethanol / distilled water, 50/50, V / V), in an amount of 0.2 ml of ethanolic solution per 100 g bodyweight.
  • the doses administered for the products tested (new compounds of the invention and reference substances) are equimolar (2 ⁇ M / 100 g bodyweight).
  • Placebo is 0.2 ml of ethanol / distilled water mixture (aa). Ethanol being used as solvent, its effect was compared before to that of physiological saline (solute 0.9% NaCl 100) or distilled water.
  • the hydro-ethanolic solutions of the products tested were prepared extemporaneously by successive dilution of a mother solution, obtained from 20 ⁇ M of product, exactly weighed, added with 1 ml pure ethanol, shaken with ultrasound, then made up to 2 ml with 1 ml of water distilled for injection.
  • Table 1 are presented the results obtained after IM administrations of 2 ⁇ Moles of the products tested, in solution in 0.2 ml of the ethanol / distilled water mixture, per 100 g of live weight. For each chick, the volume injected is adjusted, according to the live weight 0.2 ml per 100 g bodyweight.
  • the parameters observed are the locomotor activity and the state of watch chicks for 2 hours, the equivalent of 6 theoretical cycles sleep-wake of the chick of this age. They are recorded by video camera for 120 minutes.
  • Stage 3 could correspond to phases of sleep paradoxical, with shaking of the head, for example.
  • the observation of the chicks is carried out by an observer trained with continuous video control for at least 1 hour after awakening of animals.
  • Awakening is defined by the appearance of elaborate behavior aware of research and consumption of food or drink.
  • TS Sleep Time
  • Stage 3 The Sedation Time corresponds to the sum of the times different from the active watch during the 120-minute observation period.
  • the Sleeping Time (TA) is equal (to within 1 minute) to the time necessary for transition from active standby state (stage 1) to a non-vigilant state (stages 3, 4 and 5).
  • Hypnotic and sedative effects of test products on activity diurnal chicks, 10 to 15 days old, subject to a program permanent light from birth to day 6, then to a program of alternating illumination of 12 h of day (8 h - 20 h) and 12 h of darkness (20 h - 8 h) are reported in Table 1 below.
  • test series begins at 2 p.m.
  • product tested several series of measurements were carried out on batches of 3 animals, each indicated value being the average of 1 or more lots of 3 animals.
  • the derivatives according to the invention are therefore particularly advantageous for the treatment of diseases linked to disorders of the activity of melatonin.
  • the present invention therefore relates to the derivatives of formula general I, as defined above for their use in therapy, especially for the treatment of depression and disorders psychiatric, especially stress, anxiety, depression, insomnia, schizophrenia, psychoses, epilepsy, but also for treatment of travel-related sleep disorders (jet lag), illnesses neurodegenerative of the central nervous system such as Parkinson's or Alzheimer's disease, for the treatment of cancer, or again as a contraceptive, or as an analgesic.
  • the melatoninergic analogs according to the invention are also useful for the treatment of benign prostatic hyperplasia, cancers skin, skin conditions like psoriasis, acne, yeast infections, glaucoma, as well as to increase immune resistance.
  • the present invention therefore also relates to the compositions pharmaceuticals suitable for the administration of derivatives of formula general 1, especially orally, parenterally, rectally, in the form of capsules, tablets, capsules, oral solutions, injectable solutions, including including delay forms and extended release dressings for transdermal administration of the active ingredient, nasal spray, or topical formulations (cream, emulsion, etc.), comprising a derivative of general formula 1 according to the invention and at least one acceptable excipient pharmaceutically.
  • compositions according to the invention are advantageously dosed to deliver the active ingredient in a single "take”.
  • unit doses effective are between 0.1 ⁇ g and 500 mg.
  • unit doses effective are between 0.1 ⁇ g and 100 mg.
  • the melatoninergic analogs according to the invention are also useful in cosmetics, especially for protecting the skin against aging, but also against hair loss.
  • the present invention therefore also relates to a composition cosmetic comprising a derivative of general formula I according to the invention.
  • compositions according to the invention are formulated suitably for their topical application, especially under the form of ointments, creams, emulsions, ointments, lotions, etc.

Claims (10)

  1. Derivate, die ausgewählt sind aus der Gruppe bestehend aus:
    den Derivaten der allgemeinen Formel I
    Figure 00290001
    in der
    W ein Sauerstoff- oder Schwefelatom oder einen Rest =NR12 darstellt, wobei R12 ein Wasserstoffatom, einen (C1-C6)-Alkyl-, Aryl-, Aralkylrest mit einem (C1-C6)-Alkylteil, (C3-C6)-Cycloalkylrest darstellt,
    Y --- einen Rest der Formel CR8=, CW1- oder CHR20 darstellt, wobei W1 die gleiche Definition wie W oben aufweist,
    R1 bis R4 unabhängig voneinander ein Wasserstoffatom, einen Hydroxylrest, einen (C1-C6)-Alkylrest, einen Alkoxyrest mit einem (C1-C6)-Alkylteil, einen Aryloxyrest, einen Aralkyloxyrest mit einem (C1-C6)-Alkylteil, ein Halogen oder Nitro darstellen,
    R5 ein Wasserstoffatom, einen (C1-C6)-Alkylrest, einen Arylrest, einen Aralkylrest mit einem (C1-C6)-Alkylteil, einen (C1-C6)-Perhalogenalkylrest, einen Aminorest, einen (C1-C6)-Alkylamino- oder (C1-C6)-Dialkylaminorest oder einen Alkoxyrest mit einem (C1-C6)-Alkylteil darstellt,
    R6 und R20 unabhängig voneinander ein Wasserstoffatom, einen Hydroxylrest, einen (C1-C6)-Alkylrest, einen (C3-C6)-Cycloalkylrest, einen Alkoxyrest mit einem (C1-C6)-Alkylteil, einen Aryloxyrest, einen Aralkoxyrest mit einem (C1-C6)-Alkylteil, einen (C1-C6)-Alkylthio-, Arylthio-, Ar-(C1-C6)-alkylthio-, Halogen-, Nitrorest oder eine ungesättigte aliphatische Kette (C2-C6)-Alkenyl, (C2-C6)-Alkinyl, (C1-C6)-Alkyl, Aryl, Aralkyl mit einem (C1-C6)-Alkylteil, einen (C1-C6)-Perhalogenalkylrest, einen Amino-, (C1-C6)-Alkylamino-, (C1-C6)-Dialkylamino-, Arylamino-, Diarylamino-, Aralkylaminorest mit einem (C1-C6)-Alkylteil, einen Rest der Form CV-R11 oder QCVR11, in dem V ein Sauerstoff- oder Schwefelatom oder einen Iminrest =N-R12 darstellt, R11 eine der Bedeutungen von R1 aufweist, darstellen,
    worin der Ausdruck Aryl eine Phenyl-, Thienyl-, Furanyl-, Pyridyl- oder Naphthylgruppe darstellt, die gegebenenfalls durch einen oder mehrere Substituenten substituiert ist, die aus (C1-C6)-Alkyl-, Alkoxyresten mit einem (C1-C6)-Alkylteil oder Halogen ausgewählt sind,
    Q ein Sauerstoff- oder Schwefelatom darstellt,
    R7 eine der Bedeutungen von R1 aufweist, ausser dass es nicht Hydroxyl sein kann, oder einen Rest SO2R26 darstellen kann, in dem R26 ein (C1-C6)-Alkylrest oder (C1-C6)-Halogenalkylrest, insbesondere CF3, ist,
    R8 eine der Bedeutungen von R1 aufweist und auch ein Halogenatom (Chlor, Brom, lod, Fluor), eine Gruppe Q'-CV'-R'11 darstellen kann, in der Q'V' und R'11 jeweils die gleichen sind wie QV und R11, die oben definiert sind, oder
    R5 und R6 -(CH2)m-CW' darstellen, wobei m eine ganze Zahl von 2 und 3 ist und W' die gleiche Bedeutung wie W aufweist, wobei das Carbonyl oder Thiocarbonyl -CW'- direkt mit dem Stickstoff verbunden ist und der Rest -(CH2)m seinerseits an das Carbonyl oder Thiocarbonyl der Gruppe -CW- gebunden ist,
    mit der Bedingung, dass mindestens eines von R1, R6, R7, R8, R20 einen (C1-C6)-Alkylcarbonyl- oder einen (C1-C6)-Alkylthiocarbonylrest darstellt,
    N-[2-(5-Methoxyindol-3-yl)ethyl]glutarimid (7)
    N-[2-(2-Cyclohexylcarbonyl-5-methoxyindol-3-yl)ethyl]acetamid (8)
    N-[2-(5-Methoxy-2-oxo-2,3-dihydroindol-3-yl)ethyl]glutarimid (11) und
    N-[2-(6-Acetyl-5-methoxyindol-3-yl)ethyl]acetamid (12),
    deren Racemate, deren reine Enantiomere oder deren Mischungen in allen Verhältnissen und deren therapeutisch annehmbare Salze.
  2. Derivate nach Anspruch 1, dadurch gekennzeichnet, dass mindestens einer der Substituenten R2 oder R3 von einem Wasserstoffatom verschieden ist und vorzugsweise einen Hydroxyl- oder Alkoxyrest mit einem (C1-C6)-Alkylteil, insbesondere einen Methoxyrest, darstellt.
  3. Derivate nach einem der Ansprüche 1 oder 2, dadurch gekennzeichnet, dass R1 und R4 ein Wasserstoffatom darstellen.
  4. Derivate nach den Ansprüchen 1 bis 3, dadurch gekennzeichnet, dass R5 ein (C1-C6)-Alkylrest, vorzugsweise ein Methyl- oder ein Ethylrest, oder ein Perfluormethyl-, Perfluorethyl- oder Perfluorpropylrest, vorzugsweise ein Perfluorethylrest, ist.
  5. Derivate nach einem der Ansprüche 1 bis 4, dadurch gekennzeichnet, dass R7 einen (C1-C6)-Alkylcarbonylrest darstellt.
  6. Derivate nach einem der Ansprüche 1 bis 5, dadurch gekennzeichnet, dass Y ---- einen zweiwertigen Rest der Formel CR8= darstellt und R8 ein Wasserstoffatom oder einen (C1-C6)-Alkylcarbonylrest darstellt.
  7. Derivate nach Anspruch 1, die ausgewählt sind aus den folgenden Verbindungen:
    N-[2-(1-Acetyl-5-methoxyindol-3-yl)ethyl]acetamid (1),
    N-[2-(2-Acetyl-5-methoxyindol-3-yl)ethyl]acetamid (2),
    N-[2-(2-Acetyl-5-methoxyindol-3-yl)ethyl]propionamid (3),
    N-[2-(5-Methoxyindol-3-yl)ethyl]diacetamid (4),
    N-[2-(2-Acetylindol-3-yl)ethyl]acetamid (5),
    N-[2-(1-Acetyl-2-oxo-5-methoxy-2,3-dihydroindol-3-yl)ethyl]acetamid (6),
    N-[2-(5-Methoxyindol-3-yl)ethyl]glutarimid (7),
    N-[2-(2-Cyclohexylcarbonyl-5-methoxyindol-3-yl)ethyl]acetamid (8),
    N-[2-(2-Acetyl-5-methoxyindol-3-yl)ethyl]diacetamid (9),
    N-[2-(1-Acetyl-5-methoxyindol-3-yl)ethyl]diacetamid (10),
    N-[2-(5-Methoxy-2-oxo-2,3-dihydroindol-3-yl)ethyl]glutarimid (11),
    N-[2-(6-Acetyl-5-methoxyindol-3-yl)ethyl]acetamid (12),
    N-[2-(1-Carbethoxy-2-acetyl-5-methoxyindol-3-yl)ethyl]acetamid (14),
    N-[2-(2-Acetyl-6-ethyl-5-methoxyindol-3-yl)ethyl]acetamid (15),
    N-[2-(1-Acetyl-5-methoxyindolin-3-yl)ethyl]acetamid (16),
    N-[2-(1-Acetyl-6-chlor-5-methoxyindolin-3-yl)ethyl]acetamid (17),
    N-[2-(1-Benzyloxycarbonyl-5-methoxyindolin-3-yl)ethyl]diacetamid (18),
    N-[2-(1-Trifluormethansulfonyl-5-methoxyindolin-3-yl)ethyl]diacetamid (19),
    N-[2-(6-(1-Acetyl-3-(N,N-diacetyl-2-aminoethyl)-5-methoxyindolin-2-yl)-5-methoxyindol-3-yl)ethyl]diacetamid (20),
    N-[2-(1-Carbethoxy-2-acetyl-5-methoxyindolin-3-yl)ethyl]acetamid (22).
  8. Derivate nach einem der Ansprüche 1 bis 6 für die therapeutische Verwendung als Medikament.
  9. Pharmazeutische Zusammensetzung, dadurch gekennzeichnet, dass sie ein Derivat nach einem der Ansprüche 1 bis 7 und mindestens einen pharmazeutisch annehmbaren Träger umfasst.
  10. Kosmetische Zusammensetzung, dadurch gekennzeichnet, dass sie ein Derivat nach einem der Ansprüche 1 bis 7 umfasst.
EP96928490A 1995-08-08 1996-08-07 Acylierte derivate von melatonin und dessen analoge als arzneimittel Expired - Lifetime EP0851855B9 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9509611A FR2737725B1 (fr) 1995-08-08 1995-08-08 Nouveaux derives acyles de la melatonine et d'analogues melatoninergiques, leur procede de preparation et leur utilisation en tant que medicament
FR9509611 1995-08-08
PCT/FR1996/001260 WO1997006140A1 (fr) 1995-08-08 1996-08-07 Derives acyles de la melatonine et d'analogues en tant que medicament

Publications (3)

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EP0851855A1 EP0851855A1 (de) 1998-07-08
EP0851855B1 EP0851855B1 (de) 2002-06-05
EP0851855B9 true EP0851855B9 (de) 2003-05-21

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EP (1) EP0851855B9 (de)
JP (1) JP4061658B2 (de)
CN (1) CN1118451C (de)
AR (1) AR003220A1 (de)
AT (1) ATE218547T1 (de)
AU (1) AU6823696A (de)
DE (1) DE69621626T2 (de)
DK (1) DK0851855T3 (de)
ES (1) ES2176480T3 (de)
FR (1) FR2737725B1 (de)
PT (1) PT851855E (de)
WO (1) WO1997006140A1 (de)
ZA (1) ZA966751B (de)

Families Citing this family (46)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2738818B1 (fr) * 1995-09-18 1997-12-05 Valentonine Nouveaux derives d'oxydation d'indolylalkylamines, et leur utilisation a titre de medicament
US5981550A (en) * 1997-06-05 1999-11-09 Merck & Co., Inc. Antagonists of gonadotropin releasing hormone
FR2771739B1 (fr) * 1997-11-28 2001-04-20 Adir Nouveaux composes naphtaleniques, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
FR2784375B1 (fr) * 1998-10-12 2000-11-24 Adir Nouveaux derives cycliques a chaine cycloalkylenique, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
FR2787447B1 (fr) * 1998-12-18 2001-03-23 Centre Nat Rech Scient Nouveaux derives de melatonine et medicament comprenant de tels derives
WO2000065588A1 (en) * 1999-04-22 2000-11-02 Castlewood Systems, Inc. Improved motor and spindle design
FR2792937B1 (fr) * 1999-04-27 2001-08-10 Cemaf NOUVEAUX DERIVES DE PYRROLO-(3,4-b) QUINOLEINE, LEUR PROCEDE DE PREPARATION ET LEUR UTILISATION A TITRE DE MEDICAMENT
US6306890B1 (en) * 1999-08-30 2001-10-23 Vanderbilt University Esters derived from indolealkanols and novel amides derived from indolealkylamides that are selective COX-2 inhibitors
WO2002009702A2 (en) * 2000-07-28 2002-02-07 Inspire Pharmaceuticals, Inc. Use of indole derivatives for the manufacture of a medicament for reducing intracular pressure
ES2172415B2 (es) 2000-07-28 2003-11-16 Univ Madrid Complutense Tratamiento del glaucoma y la hipertension ocular por medio de un analogo de la melatonina.
US6789040B2 (en) * 2000-08-22 2004-09-07 Affymetrix, Inc. System, method, and computer software product for specifying a scanning area of a substrate
US6638966B2 (en) * 2000-09-19 2003-10-28 University Of Iowa Research Foundation Use of melatonin analogues for induction of general anesthesia
US6552064B2 (en) * 2000-09-19 2003-04-22 University Of Iowa Research Foundation Use of melatonin for induction of general anesthesia
US7186745B2 (en) 2001-03-06 2007-03-06 Astrazeneca Ab Indolone derivatives having vascular damaging activity
JP4156825B2 (ja) * 2001-11-01 2008-09-24 株式会社ロッテ 抗鬱・抗ストレス剤及びそれを含有する組成物
US6913200B2 (en) 2002-11-20 2005-07-05 Agilent Technologies, Inc. Scanning parameterization for biopolymeric array scanner
WO2004085392A1 (en) * 2003-03-25 2004-10-07 Faust Pharmaceuticals Melatonin derivatives and their use for treating neurological dysfunctions
WO2004085395A1 (en) * 2003-03-25 2004-10-07 Faust Pharmaceuticals Melatonin derivatives and their use for treating neurological dysfunctions
US7361681B2 (en) * 2003-03-28 2008-04-22 Sygnis Bioscience Gmbh & Co. Kg Method of treating amytrophic lateral sclerosis using melatonin
CA2530408A1 (en) * 2003-06-25 2005-01-06 Vanderbilt University Cox-2-targeted imaging agents
US20050137247A1 (en) * 2003-12-22 2005-06-23 The Brigham And Women's Hospital, Inc. Methods and compositions for treatment of hypertension
US7674816B2 (en) * 2003-12-23 2010-03-09 Abraxis Bioscience, Llc Substituted melatonin derivatives, process for their preparation, and methods of use
FR2866335B1 (fr) * 2004-02-13 2006-05-26 Servier Lab Nouveau procede de synthese de l'agomelatine
WO2006032987A1 (en) * 2004-09-23 2006-03-30 Pfizer Products Inc. Indoline compounds and their use in the treatment of arteriosclerosis
US20060223877A1 (en) * 2005-03-31 2006-10-05 Zemlan Frank P Methods of treatment utilizing certain melatonin derivatives
US7470799B2 (en) 2005-04-22 2008-12-30 Wyeth Dihydrobenzofuran derivatives and uses thereof
FR2898358B1 (fr) * 2006-03-08 2008-05-30 Macef Sa Association d'un antagoniste du recepteur 5ht2 et d'activateur du recepteur 5ht2 par modulation allosterique et leurs utilisations comme produits medicaux
WO2007149456A2 (en) 2006-06-19 2007-12-27 Vanderbilt University Methods and compositions for diagnostic and therapeutic targeting of cox-2
FR2903103B1 (fr) * 2006-06-30 2010-08-13 Servier Lab Nouveaux derives naphtaleniques, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
FR2903102B1 (fr) * 2006-06-30 2010-08-13 Servier Lab Nouveaux derives naphtaleniques, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
FR2907451B1 (fr) * 2006-10-18 2008-12-12 Servier Lab "nouveaux derives indoliques, leur procede de preparation et les compositions pharmaceutiques qui les contiennent"
JP5380170B2 (ja) * 2009-06-17 2014-01-08 正徳 染井 Ｎ−アシルトリプタミンを含有する組成物
WO2013013060A1 (en) * 2011-07-19 2013-01-24 Lycus, Llc Agomelatine derivatives
EP3078374B1 (de) 2011-10-17 2019-06-19 Vanderbilt University Indomethacin-analoga zur behandlung von kastrationsresistentem prostatakrebs
WO2013067036A1 (en) * 2011-10-31 2013-05-10 Rutgers, The State University Of New Jersey Direct inhibitors of keap1-nrf2 interaction as antioxidant inflammation modulators
AR091699A1 (es) 2012-07-10 2015-02-25 Astellas Pharma Inc Derivado de indol carboxamida
JP6529958B2 (ja) 2013-04-12 2019-06-12 オブシェストヴォ・ス・オグラニチェンノイ・オトヴェトストヴェンノストジュ・“ファームエンタープライジーズ” グルタルイミド誘導体、その使用、それに基づいた医薬組成物及びグルタルイミド誘導体を製造するための方法
JP5705939B2 (ja) * 2013-09-30 2015-04-22 染井　正徳 Ｎ−アシルトリプタミンを含有する組成物
CN105085367B (zh) * 2014-05-03 2019-05-21 广东东阳光药业有限公司 取代的杂芳基化合物及其组合物和用途
RU2692239C2 (ru) * 2017-01-30 2019-06-24 Общество с ограниченной ответственностью "ОФТАМЕЛАТ" Производные 2,3-дигидро-1Н-индола, обладающие свойствами лигандов мелатониновых рецепторов, способ получения и применение
CN109251151A (zh) * 2017-07-12 2019-01-22 北京广为医药科技有限公司 N-(2-(取代-萘-1-基)乙基)取代酰胺类化合物、其制备及其用途
JP7093961B2 (ja) * 2018-02-13 2022-07-01 国立大学法人金沢大学 ストレス低減薬剤
CN114736149B (zh) * 2019-03-08 2023-04-18 哈尔滨商业大学 一种2,3-二氢色胺类化合物的合成方法
RU2751048C1 (ru) * 2020-05-29 2021-07-07 Федеральное государственное бюджетное образовательное учреждение высшего образования "Южно-Уральский государственный медицинский университет" Министерства здравоохранения Российской Федерации (ФГБОУ ВО ЮУГМУ Минздрава России) Средство в виде пленки лекарственной, содержащей мелатонин, для лечения термической травмы
WO2022115960A1 (en) * 2020-12-04 2022-06-09 Magicmed Industries Inc. Aldehyde and ketone derivatives of psilocybin and methods of using
WO2023201423A1 (en) * 2022-04-19 2023-10-26 Mindset Pharma Inc. Indoline derivatives as serotonergic agents useful for the treatment of disorders related thereto

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5093352A (en) * 1988-11-14 1992-03-03 Whitby Research, Inc. Antidepressant agents
FR2658818B1 (fr) * 1990-02-27 1993-12-31 Adir Cie Nouveaux derives a structure naphtalenique, leur procede de preparation et les compositions pharmaceutiques qui les contiennent.
US5525442A (en) * 1990-09-14 1996-06-11 Westinghouse Electric Corporation Alkali metal battery
FR2680366B1 (fr) * 1991-08-13 1995-01-20 Adir Nouveaux derives d'arylethylamines, leurs procedes de preparation et les compositions pharmaceutiques qui les contiennent.
IT1255199B (it) * 1992-07-01 1995-10-20 Franco Fraschini Farmaco sintetizzato analogo della melatonina particolarmente efficacenelle patologie che interferiscono con i ritmi circadiani
US5403851A (en) * 1994-04-05 1995-04-04 Interneuron Pharmaceuticals, Inc. Substituted tryptamines, phenalkylamines and related compounds

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CN1118451C (zh) 2003-08-20
AU6823696A (en) 1997-03-05
ES2176480T3 (es) 2002-12-01
ZA966751B (en) 1997-11-03
JPH11510804A (ja) 1999-09-21
FR2737725A1 (fr) 1997-02-14
JP4061658B2 (ja) 2008-03-19
WO1997006140A1 (fr) 1997-02-20
EP0851855A1 (de) 1998-07-08
DK0851855T3 (da) 2002-09-23
US6140372A (en) 2000-10-31
EP0851855B1 (de) 2002-06-05
FR2737725B1 (fr) 1997-10-31
PT851855E (pt) 2002-10-31
AR003220A1 (es) 1998-07-08
DE69621626D1 (de) 2002-07-11
DE69621626T2 (de) 2003-02-06
US6004991A (en) 1999-12-21
ATE218547T1 (de) 2002-06-15
CN1196049A (zh) 1998-10-14

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